Sustained release preparations have a function to control the release rate of its medicinal ingredient, and they can maintain the effective blood level of the medicinal ingredient for a long time following administration to patients. In addition, it can also reduce the frequency of administration so that the compliance and QOL (quality of life) of the patient can be improved. Further, control of a blood level of the medicinal ingredient in the range of its minimum effective level to its minimum toxic level can make assure its effectiveness and safety to the human body.
Such sustained release preparations include preparations wherein a medicinal ingredient is coated with a film and preparations of matrix type wherein a medicinal ingredient is dispersed in a matrix. Illustrative preparation forms include multiple-unit preparations and single unit preparations. These multiple-unit preparations in turn include granules and fine granules, which are composed of a number of subunits, and capsules and tablets containing granules or pellets which promptly disintegrate into subunits in the digestive tract after oral administration thereof. On the other hand, such single unit preparations include non-disintegrative matrix tablets, and tablets coated with a release-controlling film.
Multiple-unit preparations are advantageous over single unit preparations in that they have high reproducibility of movement in the digestive tract, have a lower hazardous problem of local irritation owing to their movement in a wide-spread manner through the digestive tract, and permit administration in portions [Isao Sugimoto et al., "(Seizai Kaihatsu No Jissai To Kadai (Practice and Problems in the Development of Dosable Preparations)", Chapter 3, 215-228, 1986, R & D Planning]. As a production method of multiple-unit preparations, commonly employed is a method in which granules with a medicinal ingredient contained therein are coated with a release-controlling film is commonly employed. Also proposed include a method in which ion-exchange resin beads with a medicinal ingredient bound thereon are coated with a polymer, a method in which granules with a medicinal ingredient dispersed in an enteric solid are prepared by solid dispersion, a method in which matrix-type granules or fine granules with a medicinal ingredient dispersed in a polyglycerin fatty acid ester are formed by spray chilling [Japanese Patent Laid-Open No. 223533/1990], and as a production method of sustained-release granular preparations of a dihydropyridine-type Ca channel blocker, a method in which the sustained-release granular preparations are produced by extrusion granulation while using an enteric polymer, especially a water-base latex dispersion of a methacrylic acid copolymer LD as a binder (European Patent Application No. 87118948.6 filed on Dec. 21, 1987).
However, the coating method causes a safety problem to the human body because a polymer is dissolved using an organic solvent. Further, there is another problem that cumbersome control is required because the dissolution rate of a medicinal ingredient varies by a change in the thickness of a coating film or in the size of pores present in the coating film. Moreover, the coating method is accompanied by a further problem that, if a crack is formed in the coating film, the medicinal ingredient is rapidly released. On the other hand, in the method in which matrix-type granules or fine granules are produced, production procedures and quality control are relatively easy. It is, however, accompanied by a problem that a special apparatus such as a spray-chilling drier has to be used to obtain granular preparations.
Incidentally, Japanese Language Laid-Open Publication (PCT) No. 503315/1990 discloses a process for producing sustained-release dosable preparations by blending a medicinal ingredient and a polymer having a glass transition temperature (Tg) of from 30 to 150.degree. C. into a raw material composition and forming the raw material composition into a predetermined shape, in which the raw material composition is maintained at the glass transition temperature or at a temperature higher than the glass transition temperature for a time sufficient to impart a preparation form having sustained-release property. This process, however, requires addition of the polymer after its dissolution in an organic solvent or addition of the polymer as a latex dispersion by dissolving it in an organic solvent and then emulsifying the resulting solution in water. Regarding preparation forms, its Examples also disclose only tablets. Application of this process for the production of granular preparations failed to provide the resulting preparations with fully satisfactory sustained-release property.
Accordingly, it has been desired to develop a process which makes it possible to easily produce a sustained-release granular preparations of the matrix type without using any special apparatus.